Susceptibility weighted imaging (SWI) for the assessment of iron loading in the brain of beta-thalassemia major patients

postprintThe 2010 Joint Annual Meeting of ISMRM-ESMRMB, Stockholm, Sweden, 1-7 May 2010

Paediatric hepatoblastoma and hepatocellular carcinoma: retrospective study.

OBJECTIVES: To compare and contrast clinical characteristics and outcomes of hepatoblastoma or hepatocellular carcinoma in paediatric patients. DESIGN: Retrospective study. SETTING: University teaching hospital, Hong Kong. PATIENTS AND METHODS: Medical records of 22 paediatric patients with hepatoblastoma (n=11) or hepatocellular carcinoma (n=11) admitted to Queen Mary Hospital between 1989 and 2000 were reviewed. Data gathered included demographic data, results of liver function tests, hepatitis A, B, and C titres, and alpha-foetoprotein levels, and imaging studies including chest X-ray, ultrasound study, computed tomography scan, and magnetic resonance imaging/hepatic angiogram for tumour staging and resectability. RESULTS: The mean age of patients with hepatoblastoma was 18 months (range, 5 months to 3 years), while that of patients with hepatocellular carcinoma was 10.2 years (range, 2 to 16 years). Females predominated in the hepatoblastoma group (female:male, 8:3) and males in the hepatocellular carcinoma group (male:female, 10:1). None of the patients with hepatoblastoma were hepatitis B surface antigen positive, in contrast to 64% of the hepatocellular carcinoma group. Only 45% of the hepatocellular carcinomas were resectable at presentation and this figure remained unchanged following chemotherapy. A total of 91% of hepatoblastomas were resectable, four at presentation, and a further six after chemotherapy. Tumour rupture was more common in patients with hepatoblastoma than in those with hepatocellular carcinoma (36% versus 9% of cases, respectively). Mortality rates were considerably higher among the hepatocellular carcinoma group than the hepatoblastoma group in this series. CONCLUSION: Childhood hepatoblastoma and hepatocellular carcinoma differ with respect to age and tumour stage at presentation, hepatatis B surface antigen status, tendency to rupture, chemosensitivity, and prognosis.published_or_final_versio

Long-term data on sirolimus treatment in lupus nephritis patients

Poster Session: New therapies and therapeutic targets – SLE: abstract no. 109published_or_final_versio

Pre-emptive treatment for asymptomatic serological reactivation in lupus nephritis patients – impact on clinical flare rate and renal function

P16 Poster Session: SLE Epidemiology and risk factors: abstract no. 428published_or_final_versio

Vaccines for prophylaxis of viral infections in patients with hematological malignancies.

Viral infections cause significant morbidity and mortality in patients with hematological malignancies. It remains uncertain whether viral vaccinations in these patients are supported by good evidence. We aimed to determine the effectiveness and safety of viral vaccines in patients with hematological malignancies. We searched Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL (June 2010), reference lists of relevant papers, abstracts from scientific meetings and contacted vaccine manufacturers. Randomized controlled trials (RCTs) evaluating viral vaccines in patients with hematological malignancies were included. Relative risk (RR) was used for binary data and mean difference (MD) for continuous data. Primary outcome was incidence of infection. Secondary outcomes were mortality, incidence of complications and severe viral infection, hospitalization, immune response and adverse effects. Fixed-effect model was used in meta-analyses. Eight RCTs were included, with 305 patients in the intervention groups and 288 in the control groups. They evaluated heat-inactivated varicella zoster virus (VZV) vaccine (two trials), influenza vaccines (five trials) and inactivated poliovirus vaccine (IPV) (one trial). Seven trials had high and one trial had moderate risk of bias.VZV vaccine might reduce herpes zoster compared to no vaccine (RR 0.54, 95% CI 0.3 to 1.0, P=0.05), but not statistically significant. Vaccination also demonstrated efficacy in immune response but frequently caused local adverse effects. One trial reported severity score of zoster, which favored vaccination (MD 2.6, 95% CI 0.94 to 4.26, P=0.002).Two RCTs compared inactivated influenza vaccine with no vaccine and reported lower risk of lower respiratory infections (RR 0.39, 95% CI 0.19 to 0.78, P=0.008) and hospitalization (RR 0.17, 95% CI 0.09 to 0.31, P<0.00001) in vaccine recipients. However, vaccine recipients more frequently experienced irritability and local adverse effects. There was no significant difference in seroconversion between one and two doses of influenza vaccine (one trial), or between recombinant and standard influenza vaccine (one trial), or influenza vaccine given with or without re-induction chemotherapy (one trial).The IPV trial comparing vaccination starting at 6 versus 18 months after stem cell transplant (SCT) found no significant difference in seroconversion. Inactivated VZV vaccine might reduce zoster severity in adult SCT recipients. Inactivated influenza vaccine might reduce respiratory infections and hospitalization in adults with multiple myeloma or children with leukemia or lymphoma. However, the quality of evidence is low. Local adverse effects occur frequently. Further high-quality RCTs are needed.link_to_subscribed_fulltex

Sex differences in gene expression and proliferation are dependent on the epigenetic modifier HP1γ

Summary Sex differences in growth rate in very early embryos have been recognized in a variety of mammals and attributed to sex-chromosome complement effects as they occur before overt sexual differentiation. We previously found that sex-chromosome complement, rather than sex hormones regulates heterochromatin-mediated silencing of a transgene and autosomal gene expression in mice. Here, sex dimorphism in proliferation was investigated. We confirm that male embryonic fibroblasts proliferate faster than female fibroblasts and show that this proliferation advantage is completely dependent upon heterochromatin protein 1 gamma (HP1γ). To determine whether this sex-regulatory effect of HP1γ was a more general phenomenon, we performed RNA sequencing on MEFs derived from males and females, with or without HP1γ. Strikingly, HP1γ was found to be crucial for regulating nearly all sexually dimorphic autosomal gene expression because deletion of the HP1γ gene in males abolished sex differences in autosomal gene expression. The identification of a key epigenetic modifier as central in defining gene expression differences between males and females has important implications for understanding physiological sex differences and sex bias in disease

The physiological bases of hidden noise-induced hearing loss: protocol for a functional neuroimaging study

Background: Rodent studies indicate that noise exposure can cause permanent damage to synapses between inner hair cells and high-threshold auditory nerve fibers, without permanently altering threshold sensitivity. These demonstrations of what is commonly known as “hidden hearing loss” have been confirmed in several rodent species, but the implications for human hearing are unclear. Objective: Our Medical Research Council (MRC) funded programme aims to address this unanswered question, by investigating functional consequences of the damage to the human peripheral and central auditory nervous system that results from cumulative lifetime noise exposure. Behavioral and neuroimaging techniques are being used in a series of parallel studies aimed at detecting hidden hearing loss in humans. The planned neuroimaging study aims to (1) identify central auditory biomarkers associated with hidden hearing loss, (2) investigate if there are any additive contributions from tinnitus or diminished sound tolerance, which are often comorbid with hearing problems, and (3) explore the relation between subcortical functional Magnetic Resonance Imaging (fMRI) measures and the auditory brainstem response (ABR). Methods: Individuals aged 25 to 40 years with pure tone hearing thresholds ≤ 20 dB HL over the range 500 Hz to 8 kHz and no contraindications for MRI or signs of ear disease will be recruited into the study. Lifetime noise exposure will be estimated using an in-depth structured interview. Auditory responses throughout the central auditory system will be recorded using ABR and fMRI. Analyses will focus predominantly on correlations between lifetime noise exposure and auditory response characteristics. Results: This article reports the study protocol. The programme grant was awarded in July 2013. Enrollment for the study described in this protocol commenced in February 2017 and was completed in December 2017. Results are expected in 2018. Conclusions: This challenging and comprehensive study will have the potential to impact diagnostic procedures for hidden hearing loss, enabling early identification of noise-induced auditory damage via the detection of changes in central auditory processing. Consequently, this will generate the opportunity to give personalized advice regarding provision of ear defense and monitoring of further damage, thus reducing the incidence of noise-induced hearing loss

Communication style and exercise compliance in physiotherapy (CONNECT). A cluster randomized controlled trial to test a theory-based intervention to increase chronic low back pain patients’ adherence to physiotherapists’ recommendations: study rationale, design, and methods

Physical activity and exercise therapy are among the accepted clinical rehabilitation guidelines and are recommended self-management strategies for chronic low back pain. However, many back pain sufferers do not adhere to their physiotherapist’s recommendations. Poor patient adherence may decrease the effectiveness of advice and home-based rehabilitation exercises. According to self-determination theory, support from health care practitioners can promote patients’ autonomous motivation and greater long-term behavioral persistence (e.g., adherence to physiotherapists’ recommendations). The aim of this trial is to assess the effect of an intervention designed to increase physiotherapists’ autonomy-supportive communication on low back pain patients’ adherence to physical activity and exercise therapy recommendations. \ud \ud This study will be a single-blinded cluster randomized controlled trial. Outpatient physiotherapy centers (N =12) in Dublin, Ireland (population = 1.25 million) will be randomly assigned using a computer-generated algorithm to either the experimental or control arm. Physiotherapists in the experimental arm (two hospitals and four primary care clinics) will attend eight hours of communication skills training. Training will include handouts, workbooks, video examples, role-play, and discussion designed to teach physiotherapists how to communicate in a manner that promotes autonomous patient motivation. Physiotherapists in the waitlist control arm (two hospitals and four primary care clinics) will not receive this training. Participants (N = 292) with chronic low back pain will complete assessments at baseline, as well as 1 week, 4 weeks, 12 weeks, and 24 weeks after their first physiotherapy appointment. Primary outcomes will include adherence to physiotherapy recommendations, as well as low back pain, function, and well-being. Participants will be blinded to treatment allocation, as they will not be told if their physiotherapist has received the communication skills training. Outcome assessors will also be blinded. \ud \ud We will use linear mixed modeling to test between arm differences both in the mean levels and the rates of change of the outcome variables. We will employ structural equation modeling to examine the process of change, including hypothesized mediation effects. \ud \ud This trial will be the first to test the effect of a self-determination theory-based communication skills training program for physiotherapists on their low back pain patients’ adherence to rehabilitation recommendations. Current Controlled Trials ISRCTN63723433\u

Enterococcus faecalis Adapts to Antimicrobial Conjugated Oligoelectrolytes by Lipid Rearrangement and Differential Expression of Membrane Stress Response Genes.

Conjugated oligoelectrolytes (COEs) are emerging antimicrobials with broad spectrum activity against Gram positive and Gram negative bacteria as well as fungi. Our previous in vitro evolution studies using Enterococcus faecalis grown in the presence of two related COEs (COE1-3C and COE1-3Py) led to the emergence of mutants (changes in liaF and liaR) with a moderate 4- to16-fold increased resistance to COEs. The contribution of liaF and liaR mutations to COE resistance was confirmed by complementation of the mutants, which restored sensitivity to COEs. To better understand the cellular target of COEs, and the mechanism of resistance to COEs, transcriptional changes associated with resistance in the evolved mutants were investigated in this study. The differentially transcribed genes encoded membrane transporters, in addition to proteins associated with cell envelope synthesis and stress responses. Genes encoding membrane transport proteins from the ATP binding cassette superfamily were the most significantly induced or repressed in COE tolerant mutants compared to the wild type when exposed to COEs. Additionally, differences in the membrane localization of a lipophilic dye in E. faecalis exposed to COEs suggested that resistance was associated with lipid rearrangement in the cell membrane. The membrane adaptation to COEs in EFC3C and EFC3Py resulted in an improved tolerance to bile salt and sodium chloride stress. Overall, this study showed that bacterial cell membranes are the primary target of COEs and that E. faecalis adapts to membrane interacting COE molecules by both lipid rearrangement and changes in membrane transporter activity. The level of resistance to COEs suggests that E. faecalis does not have a specific response pathway to elicit resistance against these molecules and this is supported by the rather broad and diverse suite of genes that are induced upon COE exposure as well as cross-resistance to membrane perturbing stressors

Paclitaxel induces immunogenic cell death in ovarian cancer via TLR4/IKK2/SNARE-dependent exocytosis

Emerging evidence shows that the efficacy of chemotherapeutic drugs are reliant on their capability to induce immunogenic cell death (ICD), thus transforming dying tumor cells into antitumor vaccines. We wanted to uncover potential therapeutic strategies that target ovarian cancer by having a better understanding of the standard-of-care chemotherapy treatment. Here, we showed in ovarian cancer that paclitaxel induced ICD-associated DAMPs (i.e. damage-associated molecular patterns, such as CALR exposure, ATP secretion and HMGB1 release) in vitro and elicited significant antitumor responses in tumor vaccination assays in vivo. Paclitaxel-induced TLR4 signaling was essential to the release of DAMPs, which lead to the activation of NF-κB-mediated CCL2 transcription and IKK2-mediated SNARE-dependent vesicle exocytosis, thus exposing CALR on the cell surface. Paclitaxel induced ER stress, which triggered PERK activation and eIF2α phosphorylation independent of TLR4. Paclitaxel chemotherapy induced T cell infiltration in ovarian tumors of the responsive patients; CALR expression in primary ovarian tumors also correlated with patients' survival and patient response to chemotherapy. These findings suggest that the effectiveness of paclitaxel relied upon the activation of antitumor immunity through ICD via TLR4 and highlighted the importance of CALR expression in cancer cells as an indicator of response to paclitaxel chemotherapy in ovarian cancer